The role of RECK in the pathogenesis of nonalcoholic steatohepatitis

Abstract

Reversion-inducing cysteine-rich protein with Kazal motifs, or RECK, is a cell surface-anchored glycoprotein and a critical regulator of the extracellular matrix (ECM). It has been examined extensively as an anti-metastatic peptide in the field of oncology, though its role in regulating inflammation and fibrogenesis has recently been postulated. As both inflammation and fibrosis are inherent in the pathology of nonalcoholic steatohepatitis (NASH), this dissertation explores the potential of RECK to serve as a hepatoprotective agent. NASH is a growing medical concern across the globe, for which there are currently no therapeutics available. Studies here show RECK is downregulated in the liver tissue of individuals with progressive NASH. Furthermore, utilizing transgenic rodent models, RECK is demonstrated to play a regulatory role in the development of NASH. Mechanistically, RECK may be exerting these effects through the ADAM10/ADAM17-AREG-EGFR signaling axis, as alterations in this pathway correlated with experimental manipulations of RECK. Furthermore, experiments here revealed hepatic stellate cells (HSCs) to be downstream targets in this process, as exposure to exogenous AREG induced a pro-fibrotic activation phenotype in these cells. This dissertation thus demonstrates the importance of hepatocellular RECK and attempts to provide a mechanistic explanation for this novel finding. Thus, RECK is identified as a potential therapeutic target which may be utilized in the treatment of NASH.